Significance: The care and outcome of the patient with end stage renal disease (ESRD) on chronic hemodialy- sis is directly dependent on their hemodialysis access. Regional and national indicators promote the placement of arteriovenous fistulae (AVF). However, there are numerous complications of AVF, with cephalic arch stenosis (CAS) one of the leading causes of access failure in patients with a brachiocephalic fistula (BCF). Objectives: The long-term goal is to develop methods and procedures that will improve dialysis access by improving the patency of BCF and reducing the number of post-fistula procedures required to maintain such access. The immediate goal is to determine the factors that lead to the development of CAS in ESRD patients with BCF. A better understanding of these factors will 1) guide alternative designs for BCF that minimize risk of CAS, 2) guide clinical management to minimize the risk of hemodynamic parameters causing CAS, 3) establish a surveillance protocol to detect early signs of CAS or changes in hemodynamic parameters that would foster CAS, and 4) identify patients for whom BCF would not be ideal. Methods: Using a combined clinical and computational investigation, a means of predicting the risk of CAS in patients with planned fistula access is sought. Patients with ESRD requiring BCF access will be enrolled by written consent with baseline and then protocol venograms and Dopplers done at approximately 12 month intervals up to 36 months. Hemodynamic parameters (HDP) will be obtained using computational fluid dynam- ics (CFD) to determine which correlate with the development of CAS. The feasibility of this approach has been demonstrated in carrying out the preliminary studies. The results of the study will be interpreted by comparing wall shear stress (WSS), and other HDP, and geometry between those that do, and do not, develop CAS using life table and regression analysis. Other co-variates that will be analyzed include diabetes, age, sex, type and characteristics of anastomosis. The specific aims are: Aim 1: Observe a cohort of BCF subjects over time with protocol venograms and Dopplers and calculate WSS, along with other HDP, using CFD in order to perform a life table analysis to estimate the effect of WSS on time to CAS. Because diabetes may affect this outcome, diabetic and non-diabetic patients will be studied. The large-scale prospective study will be augmented by a small-scale sub study involving a subset of the larger cohort. These patients will be subject to more detailed imaging and CFD in order to elucidate the mechanisms leading to IH and venous remodeling in the cephalic arch. The prospective design of the trial with arteriovenous fistulae (AVF) placement will allow cephalic vein tissue samples to be saved for pathologic review of histology and assay for cytokines and growth factors in a subsequent study. Aim 2: In the same subjects as Aim 1, measure venous radius and cephalic arch angle over time and derive predictive functions of time, inlet pressure, anastomosis type, and initial arch angle. PUBLIC HEALTH RELEVANCE: While arteriovenous fistulae provide the best hemodialysis access available, the failure rate is unacceptably high and contributes to billions of dollars spent annually to place and maintain access for end stage renal disease (ESRD) patients. Regional and national agencies are greatly concerned that fistulae rates across the nation are dropping, contributing to poor outcomes and additional expense. Through a combined clinical and computational approach, this research will target a patient population having very poor outcomes with the immediate goal of improving understanding of factors that cause access failure and the long-term goal of developing improved clinical management protocols for ESRD patients on hemodialysis.